Cancer Prevention and Therapeutics: Panax Ginseng
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Review Panax ginseng and Cancer
Cancer Prevention and Therapeutics:
Panax Ginseng
Steve Helms, ND
Abstract Many herbal products are often mistak-
Panax ginseng has been used as a medicinal enly called ginseng. These include P.
plant in China for thousands of years. Current quinquefolium (American ginseng), from the
use in Western countries has been diverse, with northeastern parts of the United States and Canada;
focused research on cancer therapeutics. P. P. notoginseng, from Yun-nan Province in China
ginseng apparently mitigates cancer through and northern Vietnam; P. vietnamensis, from cen-
anti-inflammatory, antioxidant, and apoptotic tral Vietnam; P. japonicus, from Japan; and P.
mechanisms to influence gene expression. pseudoginseng, from the Himalayan region. Add-
Additional mechanisms of investigation include ing to the confusion, other botanical medicines are
influence on neurotransmission and commonly called ginseng that do not belong to
immunosurveillance. Low toxicity and positive the same family as P. ginseng – Eleutherococcus
studies in concomitant use with other senticosus (Siberian ginseng) and Pfaffia
chemotherapeutic agents is promising. paniculata (Brazilian ginseng). Each so-called
Although there is no conclusive evidence of P. “ginseng,” however, ranges widely in both simi-
ginseng curing cancer, research has larity and disparity to the constituents of P. gin-
continually found tumor inhibition, especially seng, and despite any overlap observed in their
in the promotion and progression phases. actions, the traditional uses and more current stud-
(Altern Med Rev 2004;9(3):259-274) ies illuminate many distinctive therapeutic appli-
cations.
Introduction
The root and rhizome of Panax ginseng Biochemistry
C.A. Meyer (Araliaceae) has been used as a medi- The active principals of P. ginseng include
cine by the people of Eastern Asia for at least 2,000 saponins, polysaccharides, flavonoids, and vola-
years. Native to Korea and northeastern China, this tile oils. In cancer therapeutics the saponins and
red-berried plant, commonly called Korean gin- polysaccharides have engendered the greatest in-
seng, is now cultivated throughout the world. It vestigation.
appears in the pharmacopoeias of several coun- Acidic polysaccharides (10,000-150,000
tries including China, Japan, Germany, Austria, MW) have been observed to have
the United Kingdom, and France, and is often immunomodulating and antiproliferative effects
employed for cancer, diabetes mellitus, and car- in tumor cell lines. Readily soluble in water, these
diovascular concerns. As in the past, P. ginseng is polysaccharides contain various sugar moieties,
still thought of as a panacea, perpetuated by its uronic acid, and less than five-percent protein by
name panax, meaning “cure all” in Greek. For weight.
these reasons P. ginseng is one of the most sought-
after medicines throughout the world. It was the
second-highest selling herbal supplement in the Steve Helms, ND – Technical Advisor, Thorne Research,
Inc; Associate Editor, Alternative Medicine Review; Private
United States in 2000, with gross retail sales of practice, Sandpoint, ID.
Correspondence address: Thorne Research, PO Box 25,
$US62 million.1 Dover, ID 83825
E-mail: steveh@thorne.com
Alternative Medicine Review ◆ Volume 9, Number 3 ◆ 2004 Page 259
Copyright©2004 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written PermissionPanax ginseng and Cancer Review
Table 1. Noteworthy Ginsenosides (28 are known)
Panaxadiols Panaxatriols
Key Ginsenosides
Rb1,Rb2, Rc, Rd, Rg3, Rh2 Re, Rf, Rg1, Rg2, Rh1
Metabolites
20(S)- protopanaxadiols 20(S)- protopanaxatriols
(i.e., 20(S)-Rg3) (i.e., 20(S)-Rg2 and 20(S)-Rh1)
Further Metabolites
Compound K, M1, IH901 Panaxytriol
(20-O-β-D-glucopyranosyl-20(S)- (heptadeca-1-ene-4,6-diyne-3,9,10-triol)
protopanaxadiol); Panaxydiol
Ginseng’s saponins, generally called hydrolysis of saponins4 and human intestinal bac-
ginsenosides (Rx), are emphasized in cancer teria.5-7 With the exception of ginsenoside Ro,
chemoprevention and therapeutics. The primary which is an oleanane-type triterpenoid, all
ginsenosides and their metabolic cousins have a ginsenosides are the dammarane-type separated
steroid-like structure2,3 and are generated by acid
into panaxadiol and panaxatriol classes (Table 1).
In Asia, the traditional preparations
of fresh white and red ginseng have various
concentrations of ginsenosides that develop
Table 2. Concentrations of Ginsenosides with Age in complexity with age (Table 2) and prepa-
ration. Classically, fresh ginseng is anything
picked before four years of growth. White
Years Total Saponins Rb Rg Ro ginseng (picked at 4-6 years) is peeled and
(%) (%) (%) (%) then dried, and contains high concentrations
of Rb1, Rb2, Rc, and Rd of the -diol group.
2 1.97 0.88 0.54 0.13 Red ginseng (harvested at 6 years) traverses
both ginsenoside classes speaking to libera-
3 2.20 1.03 0.62 0.17
tion of new constituents – Rh1, Rh2, and
4 4.75 2.27 1.10 0.40 Rg3 – from steaming the dry whole root.4,8
These traditional preparations generate a
5 4.60 2.08 1.19 0.21 therapeutic dose by stockpiling specific
6 3.84 1.94 0.81 0.29 metabolites for direct absorption and creat-
ing a similar composite of primed metabo-
9 3.81 2.32 0.46 0.40 lites for digestive processes to complex for
From: Liu CX, Xiao PG. Recent advances on ginseng
absorption (Figure 1).
research in China. J Ethnopharmacol 1992;36(1):27-38.
Page 260 Alternative Medicine Review ◆ Volume 9, Number 3 ◆ 2004
Copyright©2004 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written PermissionFigure 1. Metabolic Pathways of Rb1 and Rb2 by Human Intestinal Bacteria
Review
glc-glc-O glc-O Ara-Glc-O
HO Bifidobacterium sp. HO HO
Eubacterium sp.
Bifidobacterium sp.
Rb1 Rd Rb2
glc-glc-O glc-glc-O Glc-Glc-O
Fusobacterium K-60 Fusobacterium K-60
Bacteroides sp. Bacteroides sp.
Fusobacterium K-60
glc-glc-O Bacteroides sp. HO
HO HO Ara-Glc-O
Bifidobacterium sp. HO
Eubacterium sp.
glc-O
Gp-X VII HO 20(S)G-Rg3
glc-O glc-glc-O Compound O
Glc-O
Bifidobacterium
Rf2 cholerium
glc-glc-O glc-O HO
Alternative Medicine Review ◆ Volume 9, Number 3 ◆ 2004
HO HO
Gp-LXXV Rh2
HO Fusobacterium K-60 glc-O
Eubacterium sp.
Bacteroides sp.
Bifidobacterium sp.
glc-O HO
HO HO
Compound K Eubacterium sp.
Bacteroides sp.
Panaxydiol
HO Bifidobacterium sp. HO
Adapted from: Akao T, Kanaoka M, Kobashi K. Appearance of compound K, a major metabolite of ginsenoside Rb1 by intestinal bacteria, in rat
plasma after oral administration–measurement of compound K by enzyme immunoassay. Biol Pharm Bull 1998 Mar;21(3):245-249.
Bae EA, Park SY, Kim DH. Constitutive beta-glucosidases hydrolyzing ginsenoside Rb1 and Rb2 from human intestinal bacteria. Biol Pharm Bull
2000;23(12):1481-1485.
Page 261
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Panax ginseng and CancerPanax ginseng and Cancer Review
tion methods, and
Figure 2. The Continuum of Carcinogenesis
the interaction of
individual varia-
Initiation Promotion Progression tion of digestive
processes that, in
the case of
Antiapoptotic
ginsenosides, di-
versify and con-
Antiapoptotic
Transformed cell
agents Cancer centrate constitu-
ents.
Growth factors
Growth Panax
inhibitors
Ginseng and
the Phases of
Proangiogenic
Antiangiogenic Cancer:
agents
Mechanisms
of Action
Chemoprevention
A search
of PubMed for
Adapted from: Tsao AS, Kim ES, Hong WK. Chemoprevention of cancer. CA Cancer J “cancer,” “tu-
Clin 2004;54(3):150-80. mor,” and “Panax
ginseng” yields
over 200 articles,
A 1994 comparison study found that wild, signaling the progressive search for help in a so-
harvested plants contain more of the Rg, Rd, and ciety that has just been informed the current five-
Re fractions, while cultivated plants possess a year survival rate with cancer is 64 percent, up
greater total ginsenoside content and Rb fraction.9 from 50 percent in 1975.15
In a related study, cultured tissue cells of P. gin- From the initiation of cancer, pathogen-
seng rarely contained half the fractional constitu- esis proceeds to promotion until progression. Ini-
ents of the cultivated plant.10 In 2003 the World tiation phase is rapid (within hours to days) where
Health Organization’s new guidelines list P. gin- irreversible DNA changes occur that are success-
seng as endangered due to overharvesting.11 The fully perpetuated via mitosis. Promotion stage may
given scarcity of natural ginsenosides has take years or decades to establish an actively pro-
prompted the search for routes of synthesis from liferating premalignant lesion. While in the pro-
more accessible products. The common birch, gression phase, new clones with increased prolif-
Betula alba L. (Betulaceae), contains erative capacity, invasiveness, and metastatic po-
betulafolienetriol that has been used as a starting tential are produced within a narrow window, per-
compound in at least one study to prepare semi- haps within a year (Figure 2).16
synthetic ginsenosides.12 The result of successive mutations, can-
The standardization of ginseng formula- cer establishes a state of disharmonious intercel-
tions varies in concentration from 4-7 percent lular communication. As the discord widens, the
ginsenosides (calculated as ginsenoside Rg1),13 cell becomes less capable of inducing apoptosis
although polysaccharides may need to be added (programmed cell death) to quell the escalating
as an additional reference point in specific cancer cellular chaos. Immune cells are therein deflected
preparations.14 In both cases the bioavailable dose from surveillance and/or overrun by the cascade
is a function of horticultural variables, prepara-
Page 262 Alternative Medicine Review ◆ Volume 9, Number 3 ◆ 2004
Copyright©2004 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written PermissionReview Panax ginseng and Cancer
of dividing cells, unable to restore order by in- reduced 29 and 75 percent, respectively. 24
ducing apoptosis or even necrosis (cell death with Different ages and types of ginseng were studied
inflammation) in these errant cells. This cumula- with benzo(a)pyrene, noting more significant lung
tive loss in intracellular and intercellular commu- anticarcinogenic effects with red ginseng than
nication is incremental in malignant cells and is fresh ginseng.25 It was further noted that Rg3 and
referred to as chemotolerance. Chemotolerance Rg5 demonstrated significant reductions in
first stops the cellular defenses and thereafter im- benzo(a)pyrene-induced adenocarcinoma, while
pedes the success of immune cells, chemotherapy, Rh2 did not reach significance26 Inhibition was
and radiation. also found in lung tumors induced by
Fortunately, surgery has become a suc- dimethylbenz(a)anthracene in mice.27 Bespalov
cessful treatment for cancer, to the degree that 90 has shown strong inhibitory effects on the
percent of cancer-related deaths are due to non- development of rat mammary adenocarcinoma
primary metastatic growths.17 It is now understood induced by methyl-N-nitrosourea and N-ethyl-N-
that many of these unreachable growths develop nitrosourea administration, as well as in DMBA-
from more than one aberrant cell line. Tumors induced uterine and vaginal tumors.28
consisting of more than one genetic cell line are Other investigations that use inducers of
explained by field carcinogenesis, which speci- cytotoxicity suggest the efficacy of P. ginseng
fies that different cells within a tissue may mutate extracts in cancer treatment.29,30 Despite dose-de-
distinctively from each other due to disparities in pendent antigenotoxic properties in extracts31 and
input interpretation.18 Subsequent post-surgical metabolites,32 the reasons for reduced carcinogen-
treatment may be complicated by dissimilar esis with concomitant use of P. ginseng are un-
chemotolerance between cell lines, thwarting che- known, although genetic ties may have connec-
motherapy and radiation. Therefore, success in tion with ginseng’s reduction in inflammation and
cancer care is continually dependent on develop- oxidizing radicals.
ment of specific and even multifaceted therapies.
Mitigating Anti-inflammatory
Mitigating DNA Damage Carcinogenesis
Inducing Differentiation Repeated insult by inflammatory pro-
Ginseng’s induction of repair or reverse cesses has long been implicated in all phases of
transformation of cells into more differentiated cancer.18 Cyclooxygenase-2 (COX-2), omnipres-
(genetically stable) cells has been noted in ent in inflammatory processes, releases inflamma-
hepatoma,19,20 melanoma,21,22 and teratocarcinoma tory metabolites and reactive elements, and is in-
cells.23 However, these recognized changes in gene duced by growth factors, carcinogens, and
expression have not, in and of themselves, shown oncogenes.33 Recent studies have shown that the
promising avenues in chemoprevention or thera- 20(S)-protopanaxatriols as well as Rg3 inhibit in-
peutics. duced COX-2 expression. This process has been
attributed to inactivation of nuclear factor-kappaB
Reduced Effects from Chemical (NF-κB), a transcription factor whose activation
Carcinogens inhibits the cell death signaling of oncogenic ras.34-
36
Reduction in induced carcinogenesis by Inducible nitrous oxide synthetase (iNOS) is
various chemical carcinogens has been well another inflammatory enzyme curtailed by this
documented. Yun et al found red ginseng reduced down-regulation of NF-κB.37-38 Finally, a deriva-
9,10-dimethyl-1,2-benzanthracene (DMBA) tive of Rb1 and Rb2, often called Compound K,
cancer cell infiltration by 63 percent. With reduces inflammation39 and has been found to have
urethane exposure, red ginseng availed a 22- a stronger inhibitory effect on histamine release
percent decrease in lung adenoma, while aflatoxin than disodium cromoglycate – an anti-allergy
B1-induced lung adenoma and hepatoma were preparation.40
Alternative Medicine Review ◆ Volume 9, Number 3 ◆ 2004 Page 263
Copyright©2004 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written PermissionPanax ginseng and Cancer Review
associated with
Figure 3. Signals Inciting Apoptosis
changes in gene
expression require
Apoptosis caspase activation
(cell death) through two main
pathways. 47 The
Homeostatic signals Other signals first involves the
interaction of a
Activation Induced death receptor with
Cytotoxins
(e.g., excess glucocorticoids) its ligand, and the
second depends on
the participation of
Inactivation Induced
mitochondria
Immune Mediated
(e.g., deficiency of growth factors) involving pro- and
anti-apoptotic
members of the Bcl-
Adapted from: Eastman A. Apoptosis: a product of programmed and unprogrammed 2 family (Figures 4
cell death. Toxicol Appl Pharmacol. 1993 Jul;121(1):160-4.
and 5).16
Rb1 me-
tabolites (Rh2,
Antioxidant Chemoprevention Compound K, and panaxydiol) have been shown
The antioxidant activities of P. ginseng to encourage apoptosis by inducing caspase-3
also help explain its DNA-preserving qualities without any known activation of caspase-8.48-50
with respect to chemical carcinogens and inflam- Recently, however, Compound K was noted to
mation. Ginseng extracts have been shown to scav- initiate the caspase-8 model of apoptosis and has
enge reactive oxidative species (ROS) 41-43
as well produced a link between caspase-3 and caspase-8
as attenuate lipid peroxidation.34,41,44 Panaxadiol by an amplification loop perhaps initiated by cy-
ginsenosides (particularly Rb2), but not total sa- tochrome-c. 51 Interestingly, the loss of cyto-
ponins, have also been found to up-regulate the chrome-c from the mitochondrial membrane has
transcription of other known antioxidant enzymes been shown to be a function of pro-apoptotic Bcl-
(superoxide dismutase and catalase) by two- to 2 proteins,52 although no affect on Bcl-2 expres-
three-fold in human hepatoma cells.45 Rb3, Rb1, sion has been found with Rh2 and Compound
and Rc are antioxidants that, alone or in combina- K.50,53 A further conundrum is the ability of Rh2
tion, show significant synergistic interaction with to activate the caspase pathway in a Bcl-XL-inde-
alpha-tocopherol (aTOC). With the exception of pendent manner, suggesting additional apoptotic
Rg1, the 20(S)-protopanaxatriols show synergis- induction pathways available to ginsenosides.53
tic antioxidant interaction with aTOC. All Other studies support the use of Rb1 me-
ginsenoside antioxidants have a sugar at position tabolites for inducing programmed cell death.
6, and a pro-oxidant molecule results when glu- First, Compound K produces apoptosis in cells
cose is not bound to position 20. Rg3, Rd, and otherwise safeguarded from apoptosis by fibro-
Rh2 have pro-oxidative effects when used alone blast growth factor over-expression.54 Second,
or in combination with aTOC. 42,43 caspase-induced apoptosis is promoted by the ad-
ditional ginsenoside actions of inducing cyclin-
Induction of Apoptosis dependent kinases to depolarize the mitochondrial
Apoptosis can be induced by immune membrane (panaxydiol)53,55 and by the concomi-
cells and cytotoxins, and by changes in tant production of ROS (Rh2).53 Finally, these Rb1
homeostatic signals (Figure 3).46 The mechanisms metabolites have induced known promoters of
Page 264 Alternative Medicine Review ◆ Volume 9, Number 3 ◆ 2004
Copyright©2004 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written PermissionReview Panax ginseng and Cancer
apoptosis, including the cleav- Figure 4. Regulation of the Apoptotic Pathways:
age of poly-ADP ribose poly- The Extrinsic Pathway
merase (PARP); the up-regula-
tion of Bax, Bid, p53, p21, and Extrinsic pathway Classic pathway
p27 proteins; and the decreased
L Plasma
expression of c-myc and cyclin Rb1 metabolites membrane
D, E and A kinases. 48-51,55-59 (The
inducing effects of P. ginseng in L R
all these studies were abrogated
Caspase 8 Propase 8
by inhibitors verifying R Inner mitochondrial
ginsenoside action.) tes membrane
c tivaase 3 Bid
A sp Effector
Ca caspases
Inhibition of
Caspase
Proliferation activation
tBid
AMPs
The proliferation phase, Apoptosis Outer mitochondrial
membrane
including tumor-cell migration,
invasion, and metastasis, is Bid = proapoptotic Bcl-2 family member; tBid = truncated Bid; AMPs = proapoptotic
mitochondrial proteins
modulated by neurotransmitters
From: Sun SY, Hail N Jr, Lotan R. Apoptosis as a novel target for cancer chemoprevention.
and chemokines (Figure 6).17 The J Natl Cancer Inst 2004;96(9):662-72.
protopanaxadiol metabolites of
P. ginseng have been shown to
reduce catecholamine secretion through binding
to nicotinic receptors and blocking sodium influx Figure 5. Regulation of the Apoptotic
through the receptors.2 Catecholamines have been Pathways: The Intrinsic Pathway
noted as a chemo-attractant of breast carcinoma
cells59 and as an activator for the migration of co- Intrinsic pathway
lon carcinoma cells.60 The therapeutic benefit of
P. ginseng in neurotransmission warrants further Outer mitochondrial
membrane
investigation.
Bax, Bad, or Bak
P. ginseng has also been noted to reduce Bcl-2 or Bcl-XL
lung metastasis in two highly metastatic tumor cell
lines – colon 26-M3.1 and B16-BL6 melanoma; Caspase
Inner mitochondrial
membrane
Rb2 inhibits their angiogenesis.61 Rg3 inhibits the activation
AMPs
adhesion of tumor cells to extracellular matrix and
basement membrane components62,63 and, despite
inhibiting metastasis, does not change the growth
or vascularity of induced intestinal cancers.64 Apoptosis
Rb1 and its metabolite (Compound K) Permeability transition
pore complex
have shown reduction in lung metastasis in mice
injected with Lewis lung carcinoma. Compound
K was found to be twice as effective as Rb1 and AMPs
Caspase
to have almost the same antimetastatic potential activation Outer mitochondrial
as 5-fluorouracil (5-FU) – a chemotherapeutic membrane fragment
agent. Because of the potential toxicity of 5-FU,
Compound K may provide promising long-term AMPs = proapoptotic mitochondrial proteins
therapy, given its low toxicity – LD50 > 5g/kg. 65 From: Sun SY, Hail N Jr, Lotan R. Apoptosis as a novel target for
cancer chemoprevention. J Natl Cancer Inst 2004;96(9):662-72.
Alternative Medicine Review ◆ Volume 9, Number 3 ◆ 2004 Page 265
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Figure 6. Neurotransmitters and Chemokines as cells showed Rh2 suppression of tumor
Regulators of Metastasis growth in the initiation stage.66
Psychosocial Inflammation
Immunomodulation
factors or infection No direct evidence confirms the
cancer therapeutics of P. ginseng
through immunomodulation. However,
Neuroendocrine Immune system Other neurotransmitter
system lymph organs and chemokine-releasing recognition of the concert of immune
tissues functions that incite apoptosis in can-
cerous cells is well known. It is under-
stood that natural killer (NK) cells are
pivotal in inhibiting tumor cell prolif-
eration, and that the dynamic interplay
of both cellular and humoral immunity
e
inag
is paramount to the containment of ab-
= neurotransmitters
h dra
errant cell lines. In all these domains,
= chemokines
P. ginseng has been studied and has
Lymp
demonstrated these actions with
ginsenosides67-71 and the polysaccharide
fractions.14,72-75
The immunomodulating quali-
ties of P. ginseng may also be associ-
ated with a dampening of glucocorticoid
Bloodstream Dendritic T cell
cell levels and its activity. Mixed outcomes
Neutrophil or have been reported involving
granulocyte ginsenosides’ action as a functional ligand
Macrophage to glucocorticoid receptors.76-79Nonethe-
less, a recent rat study displays signifi-
cant reduction in serum corticosterone
levels after oral administration of whole
ginseng root at a daily dose of 100 mg/
kg body weight.80 In addition, red gin-
seng has reduced immune suppression
through lowering elevated corticoster-
Metastasizing
tumor cells one, although the mechanism is un-
known.78
Adapted from: Entschladen F, Drell TL 4th, Lang K, Joseph J, Zaenker KS.
Tumour-cell migration, invasion, and metastasis: navigation by neurotransmitters.
Lancet Oncol 2004 Apr;5(4):254-258. Applications of Ginseng or
its Constituents in Specific
Cancer Types
One study does note an increased meta-
Colon Cancer
In a dose-dependent manner (2.5 and 5.0
static potential of P. ginseng. In an experimental
mg/kg), a rat study using Rg3 found reduction in
cell line, Rh2 was found to increase metastatic po-
metastasis and tumor number as well as increased
tential, perhaps through the inhibition of Cdk2 (a
body weight.64 Red ginseng, also in a dose-depen-
cyclin-dependent kinase) producing an apoptotic-
dent manner (0.5 and 2.0 mg/kg), significantly
resistant state. The same study of BALB/c3T3
Page 266 Alternative Medicine Review ◆ Volume 9, Number 3 ◆ 2004
Copyright©2004 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written PermissionReview Panax ginseng and Cancer
reduced dysplastic crypts, although initiation Melanoma
phase inhibition was weak, limiting a prophylac- In mice, ginseng extracts and ginsenosides
tic effect.81,82 both significantly inhibited lung metastasis from
melanoma.90 Cell-line studies have shown control
Gastric Cancer of differentiation (by Rh1 and Rh2),21,22 inhibition
Red ginseng was found effective in pa- of proliferation (by red ginseng),8 inhibition of
tients with stage III gastric cancer for improving tumor angiogenesis and metastasis (by Rb2),61 and
both post-operative immunity and survival. In- most recently proliferation inhibition via up-regu-
creased CD3 and CD4 activity was reported with lation of p27 and down-regulation of c-Muc and
a five-year survival for P. ginseng patients mark- cyclin D1 (by Compound K).56
edly higher than control (68.2% versus 33.3%).
Reported dose was 4.5 g/day for the first six Ovarian Cancer
months after surgery.83 Inhibitory effects have also Rh2 was found to inhibit ovarian tumor
been found in cell-line cultures.84-86 growth in mice by induction of apoptosis and in-
creased NK-cell activity. Oral, but not intraperi-
Hepatic Cancer toneal, treatment was found effective. The dose
Red ginseng (3.78 g/kg/wk) was shown of 0.4-1.6 mg/kg was significant when given daily,
to act as a highly significant preventative to in- but not weekly. The antitumor activity was simi-
duced liver cancer. In a rat study, when taken for lar to 4 mg/kg of CDDP, while also expressing a
15 weeks prior to diethylnitrosamine exposure, significant increase in survival.91
only 14.3 percent of the rats had liver morpho-
logical changes indicative of cancer, while the Prostate Cancer
control group tallied 100-percent induction. P. gin- Rg3 has displayed growth inhibitory ac-
seng acts to decrease the speed of tumor develop- tivity as well as reduced biomarkers for prostate
ment and protect the ultrastructure of hepato- cancer (notably prostate specific antigen, andro-
cytes.87 P. ginseng metabolites (Rg3, Rg5, Rk1, gen receptors, and 5 alpha-reductase). This study
Rs5, and Rs4) have a 50-percent growth inhibi- suggests induction of apoptosis through caspase-
tion concentration in hepatoma cells – significantly 3 with the activated expression of cyclin-kinase
lower than cisplatin (CDDP).88 Other positive stud- inhibitors, p21 and p27.92
ies from 1978-2004 are noted with hepatoma cell
lines.19,20,45,48,49,51,55,57
Pulmonary Cancer
Compound K has been shown to treat
Kidney Cancer CDDP-resistant pulmonary cancer, with only a
The proliferation of renal cell carcinoma 20.3 microM concentration needed to inhibit cell
is reduced with red ginseng via a decrease in c- proliferation by 50 percent (CDDP 60.8
fos and c-jun gene expression. Only partial inhi- microM).86 Ginsenosides have shown significant
bition was produced with use of -diol or -triol frac- effect in induced lung cancers.24-26,65,93,94 A polysac-
tions independently.89 charide fraction has also shown dose-dependent
inhibition in mouse lung tumor incidence.72
Leukemia
In the human promyelocytic leukemia Other Cancer-related Uses
cells (HL-60) P. ginseng (fresh steamed) has been
shown to scavenge ROS44 and Compound K to
Ultraviolet Radiation Protection
induce apoptosis and inhibit proliferation.50 Prepared under high heat, red ginseng
extract has protected DNA from UV-induced frag-
mentation – the heralding of apoptosis.44 P. gin-
seng has also been shown to protect different cell
Alternative Medicine Review ◆ Volume 9, Number 3 ◆ 2004 Page 267
Copyright©2004 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written PermissionPanax ginseng and Cancer Review
lines from ultraviolet radiation by increasing the Ginsenosides at 2-20 mcg/mL have in-
rate of DNA repair31 and by impeding apoptosis creased tumor antigen expression,69 and associ-
by maintaining constant levels of anti-apoptotic ated antigen-guided cancer therapies may gain
Bcl-2.95 insight from studies concerning the concurrent use
of P. ginseng with immunization outcomes. Rg1
Radiation Therapy Adjunct given before general immunizations resulted in
In one study, water-extracted polysaccha- increased titers of circulating antibodies, increased
rides were injected into mice before treatment with activity of NK cells, and increased number of T-
ionizing radiation. Mice pretreated with 100 mg/ helper cells.98 Furthermore, daily administration
kg survived a radiation dose (LD50/30) 45-percent of 100 mg of four-percent standardized
more intense than control (10.93 Gy vs. 7.54 Gy). ginsenosides to patients for 12 weeks enhanced
Cytokines, including interleukins (IL-1, IL-6, IL- the efficacy of polyvalent influenza vaccine.67
12) and interferon-gamma, required for hemato-
poietic recovery were induced with enhanced T- End of Life
helper 1 function. The pretreated cells had a sig- Morphine is often used as a palliative in
nificantly increased number of bone marrow, metastatic cancer. P. ginseng exerts protective ef-
spleen cells, granulocyte-macrophage colony- fects against morphine-induced depression of B-
forming cells, and circulating neutrophils.96 cell and T-cell functions.78 Rf potentiates a kappa
opioid-induced analgesia and demonstrates the
Chemotherapy Adjunct ability to inhibit the tolerance to this analgesia in
P. ginseng has been shown to improve the a dose-dependent manner.99 This may lead to re-
delivery and action of chemotherapeutic agents duced morphine dosing and a subsequent increase
in addition to curtailing negative effects. Rc and in social functioning.
Rd are capable of significantly reversing
multidrug-resistant lymphoma cells by decreas- Toxicity and Adverse Effects
ing the expression of the mdr1 glycoprotein gene P. ginseng is unlikely to cause pharmaco-
– effectively inhibiting the efflux pump function kinetic interactions. Ginseng does not signifi-
on tumor cells.69 cantly induce cytochrome P450 (CYP) activity,100
Rg1 and Re have been shown to reverse has no effect on warfarin pharmacokinetics,101 and
P-glycoprotein (Pgp) mediated multidrug resis- the attainment of serum concentrations capable of
tance, thereby increasing the intracellular accu- modulating CYP activity in vivo seems unlikely
mulation of drugs. Furthermore, ginsenosides de- after oral administration.102 A 30-percent greater
crease the levels of Pgp affording possible long- ethanol clearance, however, may imply CYP in-
term treatment where verapamil and cyclosporin duction after alcohol dehydrogenase pathway ex-
A increase Pgp levels at maximum non-cytotoxic haustion.103
concentrations.97 Data from clinical trials suggest the inci-
Panaxytriol was found to promote cellu- dence of adverse events with ginseng is similar to
lar accumulation of mitomycin C into gastric car- placebo. Case reports reveal the following corre-
cinoma and enhance its cytotoxicity.85 In NIH3T3 lated side effects with P. ginseng intake: cerebral
mouse fibroblast cells, a mixture of -diol and arteritis (1), mastalgia (6), postmenopausal vagi-
-triol ginsenosides potentiated the apoptotic cell nal bleeding (2), metrorrhagia (1), gynaecomastia
death of the alkylating agent methyl (1), increased mania in depressive illness (1), hy-
methanesulfonate.58 In addition, Rg1 was found pertension (2), and eye symptoms associated with
to restore cyclophosphamide-impaired cellular and mydriasis and disturbed accommodation (2).104
humoral responses through activation of macro- Intake over 15 g/day resulted in deperson-
phage IL-1 production.98 alization and confusion in four patients, while in-
ducing depression in higher doses. A “ginseng
Page 268 Alternative Medicine Review ◆ Volume 9, Number 3 ◆ 2004
Copyright©2004 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written PermissionReview Panax ginseng and Cancer
abuse syndrome” has also been reported with proliferation has had limited success, with future
doses up to 15 g/day, averaging 3 g/day, with con- therapeutics on the horizon via neurotransmitter
comitant use of caffeinated beverages. Symptoms modulation. Therefore, given the short interval of
were characterized by hypertension coupled with initiation and progression (which are generally
nervousness, sleeplessness, skin eruptions, and considered irreversible), the promotion phase may
morning diarrhea in 14 patients. The syndrome provide the best target for cancer prevention.
was reported to reappear throughout the first year Much anecdotal evidence is claimed, but
of the trial, but was found to be rare at 18 and 24 there is no conclusive proof P. ginseng cures any
months.105 type of cancer. Nonetheless, evidence points to
Ginseng standardized to four-percent ginseng’s ability to limit and slow growth as well
ginsenosides has been found to increase the lu- as to enhance the ability of the immune system
menal clearance of albendazole sulfoxide, an and tumor cells to overcome chemotolerance and
antihelminthic drug, speaking to both the need for incite apoptosis. The ability of P. ginseng to in-
concern with lowering serum levels of the benz- crease the effectiveness of other chemotherapeu-
imidazole-containing drugs and the possible ad- tic agents, to act synergistically, and to help lower
junctive delivery of therapeutic agents to distur- doses and therefore adverse side effects, is increas-
bances of the bowel.106 ingly documented. Ginseng and its constituents
Studies with P. ginseng are often of short exhibit key properties that allow precancerous
duration and the majority of trials include a rela- cells to be limited to the promotion phase or to be
tively small number of patients, thus reducing destroyed altogether.
potential reports of rare and delayed adverse Despite the lack of Western-style scien-
events. Conversely, three case control studies in tific experimentation, the use of P. ginseng for
Korea with more than 10,000 patients provided cancer is well accepted in China. This herbal thera-
no information regarding adverse effects.107-109 peutic agent has only gained scientific attention
Reports of toxicity are rare in Germany and other in the West since 1972 when U.S. President Nixon
European countries in which ginseng is medically visited China and successfully opened relations.
prescribed. Indeed, both the World Health Orga- Nonetheless as P. ginseng experimentation con-
nization and the Commission E conclude that, in tinues, its recognized potential in cancer therapeu-
recommended doses (1-2 g of the crude drug or tics continues to grow.
200-600 mg of standardized extracts – calculated
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